Effects of allopurinol and febuxostat on uric acid transport and transporter expression in human umbilical vein endothelial cells

by Karel H. van der Pol, Jan Koenderink, Jeroen J. M. W. van den Heuvel, Petra van den Broek, Janny Peters, Imke D. W. van Bunningen, Jeanne Pertijs, Frans G. M. Russel, Jim Koldenhof, Wim J. Morshuis, Joris van Drongelen, Tom J. J. Schirris, Andries van der Meer, Gerard A. Rongen

Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.